Pathogenesis of fistulating Crohn's disease: a review.

Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognised complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases and overexpression of invasive molecules resulting in tissue remodelling and subsequent fistula formation. We conclude by exploring how we might utilise advancing technologies to verify and broaden our current understanding whilst exploring novel causal pathways to provide further inroads to future therapeutic targets.